Uric acid (UA) nephrolithiasis constitutes 5-8% of kidney stones in the United States. The majority of UA stones are due to acidic urinary pH titrating UA to its insoluble form. Although low urinary pH is well known to be causative, the etiology of the low pH remains lusive. This P01 has defined 6 pathophysiologic features of this disease: 1. UA stone-formers often have a clinical picture reminiscent of the metabolic syndrome. 2. The incidence of UA nephrolithiasis among diabetic stone-formers is 40% compared to about 6% incidence in the general stone-former population. 3. The low urinary pH is due to inability of the kidney to excrete the major urinary buffer ammonia leaving more H+ in its free state. 4. The acidic urinary pH in UA stone-formers is quantitatively and positively correlated with the degree of peripheral insulin resistance. 5. In a preliminary group of patients, reversal of peripheral insulin resistance by thiazolidinediones normalizes the urine pH. 6. Insulin deficiency in renal epithelial cells and insulin resistance in rodents are both associated with reduced expression and function of the epithelial transporter Na+/H+ exchanger NHE3 which contributes to excretion of ammonium. We hypothesize that 1. Insulin resistance constitute a major risk factor for UA nephrolithiasis. 2. "Renal insulin resistance" manifests as low ammonium excretion and acidic urinary pH. 3. Insulin can cause the renal acidification abnormality by multiple mechanisms; one of which is impaired NHE3 function leading to impaired ammonium excretion. Aim 1 will quantify peripheral insulin sensitivity (glucose disposal rate) and renal insulin sensitivity (urinary acidification assays) in subjects with a wide range of peripheral insulin sensitivity, and examine for quantitative correlation of the degree of peripheral vs. renal insulin resistance. However, correlation does not prove causality. Aim 2 will subject these individuals to either weight loss, piioglitazone, or both to improve their insulin resistance. Aim 3 will use the rodent model of insulin resistance (ZDF rat) and examine the pathophysiology of renal acidification defect (in addition to NHE3-mediated ammonium transport). Aim 4 will focus on the molecular mechanism of regulation of NHE3 by insulin. We have taken UA nephrolithiasis from an empirical syndrome to one where we have plausible etiologic mechanisms. This study will lay the foundation for novel concepts of renal insulin resistance and open new avenues for diagnostic and therapeutic options for UA nephrolithiasis.